Dyslipidemias pp 287-302 | Cite as

Lipodystrophies and Dyslipidemias

  • Abhimanyu GargEmail author
Part of the Contemporary Endocrinology book series (COE)


Lipodystrophies are inherited or acquired disorders characterized by selective, but variable, loss of adipose tissue. These patients are predisposed to developing insulin resistance and its complications such as premature diabetes mellitus, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, and nonalcoholic hepatic steatosis. The severity of metabolic complications in general parallels the extent of body fat loss, and patients with generalized lipodystrophies have more severe metabolic derangements compared to those with partial lipodystrophies. Advances have been made in elucidating the molecular basis of many inherited lipodystrophies and defects in genes involved in adipocyte development, differentiation, and death pathways as well as in triglyceride biosynthesis and lipid droplet formation are implicated. On the other hand, acquired lipodystrophies are mainly due to the destruction of adipocytes due to autoimmune mechanisms, drugs, or other unknown factors. Many patients develop extreme hypertriglyceridemia and chylomicronemia predisposing them to acute pancreatitis and thus need to be differentiated from those with type 1 hyperlipoproteinemia. Others with accumulation of very low-density lipoproteins (VLDL) and remnant lipoproteins may be predisposed to develop coronary heart disease. Leptin replacement therapy has been recently approved by the US Food and Drug Administration for improving metabolic complications in patients with generalized lipodystrophies. Improvement of diabetes control, use of fibrates and fish oil, and avoidance of estrogen preparations in females are key strategies to improve dyslipidemias in patients with lipodystrophies.


Lipodystrophy Hypertriglyceridemia Hepatic steatosis AGPAT2 LMNA ZMPSTE24 BSCL2 



The author would like to thank Pei-Yun Tseng for graphics.


  1. 1.
    Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350:1220–34.Google Scholar
  2. 2.
    Seip M, Trygstad O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr Suppl. 1996;413:2–28.Google Scholar
  3. 3.
    Agarwal AK, Simha V, Oral EA, et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003;88:4840–7.Google Scholar
  4. 4.
    Van Maldergem L, Magre J, Khallouf TE, et al. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet. 2002;39:722–33.Google Scholar
  5. 5.
    Garg A, Wilson R, Barnes R, et al. A gene for congenital generalized lipodystrophy maps to human chromosome 9q34. J Clin Endocrinol Metab. 1999;84:3390–4.Google Scholar
  6. 6.
    Agarwal AK, Arioglu E, De Almeida S, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002;31:21–3.Google Scholar
  7. 7.
    Magre J, Delepine M, Khallouf E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28:365–70.Google Scholar
  8. 8.
    Kim CA, Delepine M, Boutet E, et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008;93:1129–34.Google Scholar
  9. 9.
    Hayashi YK, Matsuda C, Ogawa M, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009;119:2623–33.Google Scholar
  10. 10.
    Simha V, Agarwal AK, Aronin PA et al. Novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability. Am J Med Genet A. 2008; 146A:2318–26.Google Scholar
  11. 11.
    Simha V, Garg A. Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. J Clin Endocrinol Metab. 2003;88:5433–7.Google Scholar
  12. 12.
    Rajab A, Straub V, McCann LJ, et al. Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations. PLoS Genet. 2010; 6:e1000874.Google Scholar
  13. 13.
    Shastry S, Delgado MR, Dirik E, et al. Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations. Am J Med Genet A. 2010; 152A:2245–53.Google Scholar
  14. 14.
    Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9:109–12.Google Scholar
  15. 15.
    Shackleton S, Lloyd DJ, Jackson SN, et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature genetics. 2000;24:153–6.Google Scholar
  16. 16.
    Speckman RA, Garg A, Du F, et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet. 2000;66:1192–8.Google Scholar
  17. 17.
    Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87:408–11.Google Scholar
  18. 18.
    Hegele RA, Cao H, Frankowski C, et al. PPARG F388 L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002;51:3586–90.Google Scholar
  19. 19.
    Semple RK, Chatterjee VK, O’Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest. 2006;116:581–9.Google Scholar
  20. 20.
    George S, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–8.Google Scholar
  21. 21.
    Dunnigan MG, Cochrane MA, Kelly A, Scott JW. Familial lipoatrophic diabetes with dominant transmission. A new syndrome. Q J Med. 1974;43:33–48.Google Scholar
  22. 22.
    Garg A, Peshock RM, Fleckenstein JL. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 1999;84:170–4.Google Scholar
  23. 23.
    Garg A, Vinaitheerthan M, Weatherall PT, Bowcock AM. Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene. J Clin Endocrinol Metab. 2001;86:59–65.Google Scholar
  24. 24.
    Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 2000;85:1776–82.Google Scholar
  25. 25.
    Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene. Am J Med. 2002;112:549–55.Google Scholar
  26. 26.
    Subramanyam L, Simha V, Garg A. Overlapping syndrome with familial partial lipodystrophy, Dunnigan variety and cardiomyopathy due to amino-terminal heterozygous missense lamin A/C mutations. Clin Genet. 2010;78:66–73.Google Scholar
  27. 27.
    Simha V, Garg A. Body fat distribution and metabolic derangements in patients with familial partial lipodystrophy associated with mandibuloacral dysplasia. J Clin Endocrinol Metab. 2002;87:776–85.Google Scholar
  28. 28.
    Novelli G, Muchir A, Sangiuolo F, et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet. 2002;71:426–31.Google Scholar
  29. 29.
    Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003;12:1995–2001.CrossRefPubMedGoogle Scholar
  30. 30.
    Merideth MA, Gordon LB, Clauss S, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008;358:592–604.Google Scholar
  31. 31.
    Jacob KN, Baptista F, dos Santos HG, et al. Phenotypic heterogeneity in body fat distribution in patients with atypical Werner’s syndrome due to heterozygous Arg133Leu lamin A/C mutation. J Clin Endocrinol Metab. 2005;90:6699–706.CrossRefPubMedGoogle Scholar
  32. 32.
    O’Neill B, Simha V, Kotha V, Garg A. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am J Med Genet A. 2007;143:1421–30.Google Scholar
  33. 33.
    Goldblatt J, Hyatt J, Edwards C, Walpole I. Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3’ end of the FBN1 gene. Am J Med Genet A. 2011;155A:717–20.Google Scholar
  34. 34.
    Graul-Neumann LM, Kienitz T, Robinson PN, et al. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3’ terminus of the FBN1-gene. Am J Med Genet A. 2010;152A:2749–55.Google Scholar
  35. 35.
    Horn D, Robinson PN. Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene. Am J Med Genet A. 2011;155A:721–4.Google Scholar
  36. 36.
    Garg A, Xing C. De novo heterozygous FBN1 mutations in the extreme C-terminal region cause progeroid fibrillinopathy. Am J Med Genet A. 2014;164A(5):1341–5.Google Scholar
  37. 37.
    Aarskog D, Ose L, Pande H, Eide N. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes. Am J Med Genet. 1983;15:29–38.Google Scholar
  38. 38.
    Sorge G, Ruggieri M, Polizzi A, et al. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet. 1996;61:178–81.Google Scholar
  39. 39.
    Chudasama KK, Winnay J, Johansson S, et al. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet. 2013;93:150–7.Google Scholar
  40. 40.
    Dyment DA, Smith AC, Alcantara D, et al. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013;93:158–66.Google Scholar
  41. 41.
    Garg A, Hernandez MD, Sousa AB, et al. An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J Clin Endocrinol Metab. 2010;95:E58–63.Google Scholar
  42. 42.
    Agarwal AK, Xing C, DeMartino GN, et al. PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet. 2010;87:866–72.Google Scholar
  43. 43.
    Rivett AJ, Hearn AR. Proteasome function in antigen presentation: immunoproteasome complexes, Peptide production, and interactions with viral proteins. Curr Protein Pept Sci. 2004;5:153–61.Google Scholar
  44. 44.
    Torrelo A, Patel S, Colmenero I, et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol. 2010;62:489–95.Google Scholar
  45. 45.
    Ramot Y, Czarnowicki T, Maly A, et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a case report. Pediatr Dermatol. 2011;28(5)538–41 (2010:epub ahead of print).Google Scholar
  46. 46.
    Shastry S, Simha V, Godbole K, et al. A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism. J Clin Endocrinol Metab. 2010;95:E192–7.Google Scholar
  47. 47.
    Weedon MN, Ellard S, Prindle MJ, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet. 2013;45:947–50.Google Scholar
  48. 48.
    Peterfy M, Ben-Zeev O, Mao HZ, et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat Genet. 2007;39:1483–7.Google Scholar
  49. 49.
    Ullrich NF, Purnell JQ, Brunzell JD. Adipose tissue fatty acid composition in humans with lipoprotein lipase deficiency. J Investig Med. 2001;49:273–5.Google Scholar
  50. 50.
    Chen D, Misra A, Garg A. Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab. 2002;87:4845–56.Google Scholar
  51. 51.
    Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis. 2000;30(Suppl 2):S135–42.Google Scholar
  52. 52.
    Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48–62.Google Scholar
  53. 53.
    Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004;83:18–34.Google Scholar
  54. 54.
    Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine. 2003;82:129–46.Google Scholar
  55. 55.
    Savage DB, Semple RK, Clatworthy MR, et al. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab. 2009;94:10–6.Google Scholar
  56. 56.
    Hudon SE, Coffinier C, Michaelis S, et al. HIV-protease inhibitors block the enzymatic activity of purified Ste24p. Biochem Biophys Res Commun. 2008;374:365–8.Google Scholar
  57. 57.
    Bastard JP, Caron M, Vidal H, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet. 2002;359:1026–31.Google Scholar
  58. 58.
    Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000; 14:F25–32.Google Scholar
  59. 59.
    Lee H, Hanes J, Johnson KA. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry. 2003;42:14711–9.Google Scholar
  60. 60.
    Simha V, Garg A. Lipodystrophy: lessons in lipid and energy metabolism. Curr Opin Lipidol. 2006;17:162–9.Google Scholar
  61. 61.
    Gordon LB, Harten IA, Patti ME, Lichtenstein AH. Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: clues to the biology of premature atherosclerosis in Hutchinson-Gilford Progeria Syndrome. J Pediatr. 2005;146:336–41.Google Scholar
  62. 62.
    Chen L, Lee L, Kudlow BA, et al. LMNA mutations in atypical Werner’s syndrome. Lancet. 2003;362:440–5.Google Scholar
  63. 63.
    Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49:755–65.Google Scholar
  64. 64.
    Haque WA, Shimomura I, Matsuzawa Y, Garg A. Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab. 2002;87:2395–8.Google Scholar
  65. 65.
    Fujimoto T, Ohsaki Y, Cheng J, et al. Lipid droplets: a classic organelle with new outfits. Histochem Cell Biol. 2008;130:263–79.Google Scholar
  66. 66.
    Szymanski KM, Binns D, Bartz R, et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A. 2007;104:20890–95.Google Scholar
  67. 67.
    Fei W, Shui G, Gaeta B, et al. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol. 2008;180:473–82.Google Scholar
  68. 68.
    Cohen AW, Razani B, Schubert W, et al. Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes. 2004;53:1261–70.Google Scholar
  69. 69.
    Le Lay S, Hajduch E, Lindsay MR, et al. Cholesterol-induced caveolin targeting to lipid droplets in adipocytes: a role for caveolar endocytosis. Traffic. 2006;7:549–61.Google Scholar
  70. 70.
    Cortes VA, Curtis DE, Sukumaran S, et al. Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab. 2009;9:165–76.Google Scholar
  71. 71.
    Beylot M, Sautot G, Laville M, Cohen R. Metabolic studies in lipoatrophic diabetes: mechanism of hyperglycemia and evidence of resistance to insulin of lipid metabolism. Diabete Metab. 1988;14:20–4.Google Scholar
  72. 72.
    Semple RK, Sleigh A, Murgatroyd PR, et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest. 2009;119:315–22.Google Scholar
  73. 73.
    Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570–8.Google Scholar
  74. 74.
    Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. 2010;95:4291–304.Google Scholar
  75. 75.
    Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med. 2000;133:263–74.Google Scholar
  76. 76.
    Ludtke A, Heck K, Genschel J, et al. Long-term treatment experience in a subject with Dunnigan-type familial partial lipodystrophy: efficacy of rosiglitazone. Diabet Med. 2005;22:1611–3.Google Scholar
  77. 77.
    Sleilati GG, Leff T, Bonnett JW, Hegele RA. Efficacy and safety of pioglitazone in treatment of a patient with an atypical partial lipodystrophy syndrome. Endocr Pract. 2007;13:656–61.Google Scholar
  78. 78.
    Gambineri A, Semple RK, Forlani G, et al. Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin. Eur J Endocrinol/Eur Federation Endocr Soc. 2008;159:347–53.Google Scholar
  79. 79.
    Owen KR, Donohoe M, Ellard S, Hattersley AT. Response to treatment with rosiglitazone in familial partial lipodystrophy due to a mutation in the LMNA gene. Diabet Med. 2003;20:823–7.Google Scholar
  80. 80.
    Simha V, Rao S, Garg A. Prolonged thiazolidinedione therapy does not reverse fat loss in patients with familial partial lipodystrophy, Dunnigan variety. Diabetes, Obes Metab. 2008; 10:1275–6.Google Scholar
  81. 81.
    Savage DB, Tan GD, Acerini CL, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-g. Diabetes. 2003;52:910–7.Google Scholar
  82. 82.
    Javor ED, Cochran EK, Musso C, et al. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54:1994–2002.Google Scholar
  83. 83.
    Ebihara K, Kusakabe T, Hirata M, et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab. 2007;92:532–41.Google Scholar
  84. 84.
    Park JY, Javor ED, Cochran EK, et al. Long-term efficacy of leptin replacement in patients with Dunnigan-type familial partial lipodystrophy. Metabolism. 2007;56:508–16.Google Scholar
  85. 85.
    McDuffie JR, Riggs PA, Calis KA, et al. Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrinol Metab. 2004;89:4258–63.Google Scholar
  86. 86.
    Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109:1345–50.Google Scholar
  87. 87.
    Simha V, Szczepaniak LS, Wagner AJ, et al. Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. Diabetes Care. 2003;26:30–35.Google Scholar
  88. 88.
    Javor ED, Ghany MG, Cochran EK, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41:753–60.Google Scholar

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© Humana Press 2015

Authors and Affiliations

  1. 1.Division of Nutrition and Metabolic Diseases, Department of Internal MedicineUT Southwestern Medical CenterDallasUSA

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